(19) TZZ_¥Z_T (11) EP 1 669 350 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 211/58 (2006.01) C07D 401/06 (2006.01) 29.02.2012 Bulletin 2012/09 C07D 401/14 (2006.01) C07D 401/02 (2006.01) C07D 401/12 (2006.01) C07D 409/12 (2006.01) (2006.01) (2006.01) (21) Application number: 04787951.5 A61K 31/4545 A61K 31/496 A61K 31/454 (2006.01) A61K 31/4523 (2006.01) A61K 31/4535 (2006.01) A61K 31/506 (2006.01) (22) Date of filing: 21.09.2004 A61P 43/00 (2006.01) A61P 3/04 (2006.01) A61P 3/10 (2006.01) A61P 5/00 (2006.01) A61P 3/06 (2006.01) A61P 19/06 (2006.01) A61P 9/10 (2006.01) A61P 9/04 (2006.01) A61P 9/12 (2006.01) (86) International application number: PCT/JP2004/013768 (87) International publication number: WO 2005/028438 (31.03.2005 Gazette 2005/13) (54) PIPERIDINE DERIVATIVES PIPERIDINDERIVATE DERIVES DE PIPERIDINE (84) Designated Contracting States: • TOKITA, Shigeru, AT BE BG CH CY CZ DE DK EE ES FI FR GB GR c/o Tsukuba Research Institute HU IE IT LI LU MC NL PL PT RO SE SI SK TR Tsukuba-shi, Designated Extension States: Ibaraki 3002611 (JP) LT LV • KANATANI, Akio, c/o Tsukuba Research Institute (30) Priority: 22.09.2003 JP 2003330758 Tsukuba-shi, Ibaraki 3002611 (JP) (43) Date of publication of application: 14.06.2006 Bulletin 2006/24 (74) Representative: Rollins, Anthony John et al Merck Sharp & Dohme Limited (73) Proprietor: MSD K.K. European Patent Department Chiyoda-ku Hertford Road Tokyo Hoddesdon 102-8667 (JP) Hertfordshire EN11 9BU (GB) (72) Inventors: (56) References cited: • OHTAKE, N. WO-A1-2004/037257 WO-A2-02/076925 Tsukuba Res. Inst. Banyu Pharmaceutical WO-A2-02/099388 WO-A2-2004/069792 Ibaraki 300-2611 (JP) JP-A- 5 078 316 JP-A- 10 324 695 • MIZUTANI, Sayaka, JP-A- 2001 522 836 c/o Tsukuba Research Institute Tsukuba-shi Ibaraki 3002611 (JP) • YOSHIMOTO, Ryo, c/o Tsukuba Research Institute Tsukuba-shi, Ibaraki 3002611 (JP) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 669 350 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 1 669 350 B1 • DATABASECA[Online]CHEMICALABSTRACTS SERVICE, COLUMBUS, OHIO, US; LUBISCH, WILFRIED ET AL: "Preparation of 2- phenylbenzimidazoles as poly(ADP-ribose) polymerase inhibitors." XP002520491 retrieved from STN Database accession no. 2000:314677 & WO 00/26192 A1 (BASF AKTIENGESELLSCHAFT, GERMANY) 11 May 2000 (2000-05-11) • DATABASECA[Online]CHEMICALABSTRACTS SERVICE, COLUMBUS, OHIO, US; GOEL, OM P.: "Trialkylsilyl esters of 6-(substituted amino) phenyl-1, dihydro-2-oxonicotinic acid and conversion to the corresponding acid chlorides" XP002520492 retrieved from STN Database accession no. 1976:543094 & US 3 951 982 A (GOEL, OM P.) 20 April 1976 (1976-04-20) Remarks: Thefilecontainstechnicalinformationsubmittedafter the application was filed and not included in this specification 2 EP 1 669 350 B1 Description TECHNICAL FIELD 5 [0001] The present invention relates to a novel piperidine derivative, to a histamine-H3 receptor antagonist containing the novel piperidine derivative as an active ingredient thereof, and to a preventive or remedy for metabolic system diseases, circulatory system diseases, central or peripheral nervous system diseases. BACKGROUND ART 10 [0002] It has been known that, in organisms such as typically mammals, histamine that is a physiologically-active endogenous factor functions as a neurotransmitter and has extensive pharmacological activities (for example, see Life Science, 17,1975, 503 (1975)). Immunohistochemical studies have made it clear that a histamine-agonistic (producing) cell body exists in the nodal papillary nucleus in a posterior hypothalamic region and that histamine nerve fibers project 15 histamine in an extremely broad range in the brain, which supports various pharmacological effects of histamine (for example, see Journal of Comprehensive Neurology, 273, 283). The existence of histamine-agonistic nerves in the nodal papillary nucleus in a posterior hypothalamic region suggests that histamine may have an important role in control of physiological functions relating to brain functions, especially to hypothalamic functions (sleep, vigilance rhythm, incretion, eating and drinking action, sexual action, etc.) (for example, see Progress in Neurobiology, 63,637 (2001)). The existence 20 of histamine projection to the brain region that relates to vigilance sustenance, for example, to cerebral cortex suggests the role of histamine in control of vigilance or vigilance-sleep cycle. The existence of histamine projection to many peripheral structures such as hippocampus and amygdaloid complex suggests the role of histamine in control of auto- nomic nerves, emotion, control of motivated action and learning/memory process. [0003] On the other hand, when released from producing cells, histamine acts with a specific polymer that is referred 25 to as a receptor on the surface of a cell membrane or inside a target cell, therefore exhibiting its pharmacological effects for control of various body functions. Heretofore, four types of histamine receptors (H1 to H4) have been found In particular, the presence of a histamine receptor that participates in the central and peripheral nervous functions, a histamine-H3 receptor, has been shown by various pharmacological and physiological studies (for example, see Trends in Pharmacological Science, 8, 24 (1986)); and recently, human and rodent histamine-H3 receptor genes have been 30 identified and their existence has been made clear (for example, see Molecular Pharmacology, 55, 1101 (1999)). It is shown that a histamine-H3 receptor exists in the presynaptic membrane of central or peripheral neurocytes and functions as a self-receptor, therefore controlling the liberation of histamine and controlling the release of other neurotransmitters. Specifically, it is reported that a histamine-H3 receptor agonist, or its antagonist or inverse-agonist (generically referred to as antagonist) controls the release of histamine, noradrenaline, serotonin, acetylcholine or dopamine from nerve 35 ending For example, the release of these neurotransmitters is inhibited by an agonist such as (R)-(α)-methylhistamine, and the release of these neurotransmitters is promoted by an antagonist or inverse-agonist such as thioperamide (for example, see Trends in Pharmacological Science, 19,177 (1998)). Recent studies have shown that a histamine-H3 receptor has extremely high homeostatic activities (endogenous agonistic factor, e.g., activity observed in the absence of histamine) in the receptor-expressing cells/tissues or in a membrane fraction derived from the expressing cells/tissues 40 and even in living bodies (for example, see Nature, 408, 860). It is reported that these homeostatic activities are inhibited by an antagonist or an inverse-agonist. For example, a homeostatic self-receptor activity is inhibited by thioperamide or syproxyfan, and, as a result, the release of neurotransmitters from nerve ending, for example, the release and liberation of histamine from it is thereby promoted [0004] Various studies have been made for clarifying the effects of a histamine-H3 receptor. In animal experiments 45 with rats, a high-level selective inhibitor of histamine synthase (histidine decarboxylase) inhibits the vigilance of rats, which suggests that a histamine-H3 receptor may function for controlling motive vigilance. Administration of a histamine- H3 receptor agonist, (R)-(α)-methylhistamine to cats increases their deep slow-wave sleep (for example, see Brain Research, 523, 325 (1990)). Contrary to this, it has been clarified that a histamine-H3 receptor antagonist or inverse- agonist, thioperamide dose-dependently increases vigilance, and decreases slow-wave and REM sleep (see Science, 50 48,2397 (1991)). This suggests that a histamine-H3 receptor may participate in control of vigilance-sleep, and suggest a possibility that a selective histamine-H3 receptor agonist, or its antagonist or inverse-agonist may be useful for treatment of sleep disorders. Further, in animal experiments with rats, administration of histamine to the ventricle of rats inhibited their eating action, therefore suggesting that histamine may participate in control of eating action (for example, see Research, 793, 279 (1998)), and it has been clarified that thioperamide dose-dependently inhibits eating action and 55 promotes intracerebral histamine liberation (for example, see Life Science, 69, 469 (2001)). These informations suggest that a histamine-H3 receptor may participate in eating action control, further suggesting a possibility that an a histamine- H3 receptor antagonist or inverse-agonist may be useful for prevention or remedy of metabolic diseases such as eating disorder, obesity, diabetes, emaciation, hyperlipemia. In addition, in animal experiments with rats, it has been clarified 3 EP 1 669 350 B1 that administration of a histamine-H3 receptor agonist, (R)-(α)-methylhistamine to rats dose-dependently lowered their basal diastolic pressure, and its action was antagonized by a histamine-H3 receptor antagonist or inverse-agonist, thioperamide (for example, see Journal of Physiology and Pharmacology, 49, 191 (1998)). These informations